Diabetes has reached epidemic proportions in the United States resulting in expenditures of over $90B per year. The enormity of the potential market inspired many pharmaceutical companies to enter the field but success has proven difficult. The reason for this difficulty is that diabetes is a complicated disease affecting multiple organ systems including the kidneys, nervous system, and vascular system. The most severe effects of diabetes are related to long-term toxicity of high circulating glucose levels. Glucose toxicity and insulin resistance remain the greatest unmet need in the treatment of diabetes. Further, the chronic nature of diabetes requires that therapeutics present long-term safety profiles, a serious obstacle to clinical and market success. MEDROS'goal is to impact the field of diabetes by providing drugs that ameliorate the effects of insulin resistance using a different approach to drug discovery. MEDROS was founded on a proprietary platform optimized for high-throughput drug screening in situ by generating human diseases in the fruit fly Drosophila. Our whole-organism approach holds the promise of producing better safety and efficacy data than traditional pre-clinical modeling techniques with lower cost. MEDROS has licensed technology, from our academic collaborators at Washington University, to screen small- molecule drugs in a diet-induced Drosophila model system for insulin resistance and Type-2 diabetes mellitus (T2DM). This model phenocopies important biochemistry observed in human patients with T2DM, namely hyperglycemia, hyperinsulinemia, and triglyceride accumulation, and also recapitulates the endpoint outcome- shortened lifespan. As part of a large genetic screen performed by our collaborators it was discovered that knockdown of p38 kinase in specific tissue rescues flies from the effects of high sugar feeding, while whole organism knockout made the flies worse. This result suggests that tissue specific p38 inhibitors, with low systemic exposure, could be safe and effective agents against T2DM. The major objective for this Phase I SBIR proposal is to create a library of known and novel p38 kinase inhibitors and evaluate their effects on fruit flies fed a high glucose diet. A subset of these known inhibitors will be modified into novel prodrugs to explore tissue specific activation and efficacy. MEDROS'ultimate vision is to validate an entirely in situ approach to diabetes drug discovery, from fly to rodent to man. PUBLIC HEALTH RELEVANCE: Diabetes has reached epidemic proportions in the United States, resulting in expenditures approaching $100 billion per year. Glucose toxicity and insulin resistance remain perhaps the greatest unmet need in the treatment of diabetes. MEDROS owns a proprietary Drosophila model that displays metabolic defects that mimic those in patients with T2DM: hyperglycemia, hyperinsulinemia, triglyceride accumulation, and shortened lifespan. MEDROS'goal is to impact the field of diabetes not only by putting better drugs into the clinic, but doing so by developing a different approach to drug discovery utilizing high-throughput whole-organism drug screens in fruit flies with human-like diseases.